Process for preparing cepham compounds

ABSTRACT

A novel 4-(2&#39;-benzothiazolyldithio)-3-imidoazetidin-2-one of the formula ##STR1## in which X is chloro or bromo and R 2  is methylene or oxygen is ring-closed to the corresponding 3-exomethylenecepham or 3-&#34;oxo&#34; cepham by treatment with sodium or potassium iodide at a temperature of from about 40° C. to about 80° C.

This is a division of application Ser. No. 615,154, filed Sept. 19,1975, and now U.S. Pat. No. 4,024,152 issued May 17, 1977.

BACKGROUND OF THE INVENTION

The preparation of 3-exomethylenecephams has recently been reported[Chauvette, R. R., and Pennington, P. A., Journal of Organic Chemistry,38, 2994 (1973); and Chauvette, R. R., and Pennington, P. A., Journal ofthe American Chemical Society, 96, 4986 (1974)]. In conjunction withthis disclosure, it was also reported that the 3-exomethylenecephemscould be converted by ozonolysis to their corresponding 3-"oxo" cephems.These latter compounds can also be termed 3-keto cephems or, in terms oftheir tautomeric form, 3-hydroxy cephems.

It has now been discovered that 3-exomethylene-cephems and 3-ketocephamscan be prepared from a novel class of azetidin-2-ones. It is to such aclass of compounds as well as to a process for preparing3-exomethylenecephams and 3-ketocephams from these compounds that thisinvention is directed.

SUMMARY OF THE INVENTION

It is an object of this invention therefore to provide a process forpreparing a 3-exomethylenecepham or a 3-ketocepham (3-hydroxy-3-cephem)which comprises reacting a compound of the formula ##STR2## with atleast a molar ratio of sodium or potassium iodide at a temperature offrom about 40° C. to about 80° C., to produce the aforementioned3-exomethylene or 3-keto compound of the formula ##STR3## in which, inthe above formulae, R₁ is a carboxy protecting group; R is the residueof an imide derived from a dicarboxylic acid; R₂ is =CH₂ or =O; and X ischloro or bromo.

Another object of this invention relates to novel azetidin- 2-ones ofthe formula ##STR4## in which R, R₁, R₂, and X are as definedhereinabove.

DETAILED DESCRIPTION OF THE INVENTION

As delineated hereinabove, the novel azetidin-2-ones of this inventionhave the formula I above.

R₁ in the above formula I denotes a carboxy protecting group.Preferably, the carboxy protecting group is the residue of an esterfunction which is removable by acid treatment or by hydrogenation.Preferred such carboxy protecting groups include, for example, C₁ -C₄alkyl, 2-iodoethyl, benzyl, p-nitrobenzyl, succinimidomethyl,phthalimidomethyl, p-methoxybenzyl, benzhydryl, C₂ -C₆alkanoyloxymethyl, trimethylsilyl, and phenacyl.

Specific illustrations of the preferred carboxy protecting groups of theazetidin-2-ones of this invention include, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, 2-iodoethyl,benzyl, p-nitrobenzyl, succinimidomethyl, phthalimidomethyl,p-methoxybenzyl, benzhydryl, acetoxymethyl, pivaloyloxymethyl,propionoxymethyl, trimethylsilyl, phenacyl, and the like.

Highly preferred carboxy protecting groups are methyl, benzyl,p-nitrobenzyl, p-methoxybenzyl, benzhydryl, t-butyl, and trimethylsilyl.

The cyclic imide radical, defined by R taken together with thenitrogen-dicarbonyl combination to which it is bonded, can be formed byreacting the amino group of the 6-amino-penam or the 7-amino-cephamprecursor further elaborated hereinafter with a dicarboxylic acid oranhydride or other reactive variant thereof, followed by reacting theresulting derivative with a C₁ -C₄ alkyl haloformate, for example, ethylchloroformate, in the presence of an organic base. Preferably, R is C₂-C₄ alkylene, 1,2-cyclohexylene, 1,2-phenylene, 1,2-cyclohexenylene, ora substituted derivative of any of these having a substituent selectedfrom the group consisting of C₁ -C₃ alkyl, C₁ -C₃ alkoxy, nitro, fluoro,chloro, bromo, and iodo. Typically, R is the residue of a C₄ -C₁₀dicarboxylic acid, and the cyclic imide thus represented is preparedfrom such discarboxylic acid, its anhydride, or an appropriate reactivevariant thereof. Cyclic imides can be prepared, for example, from acidssuch as malonic, succinic, adipic, glutaric, phthalic, and the like, ortheir respective anhydrides, as well as fromcyclohexane-1,2-dicarboxylic, 3-cyclohexene-1,2-dicarboxylic, halogensubstituted dicarboxylic acids or anhydrides such as 4-chlorophthalic,3-iodophthalic, 4-bromophthalic, nitro substituted dicarboxylic acidsand anhydrides such as 3-nitrophthalic acid, alkyl substituteddicarboxylic acids and anhydrides such as 4-methylphthalic acid, as wellas related compounds and compounds of similar reactivities. Additionalexamples of cyclic anhydrides of the type defined are found in the priorart such as in the Journal of Organic Chemistry, 26, pp. 3365-3367(September, 1961).

The novel azetidin-2-ones of this invention are useful as intermediatesin the production of 3-exomethylenecephams as well as3-hydroxy-3-cephems. The azetidin-2-ones of this invention are preparedindirectly from 2β-halomethyl-3α-methylpenams which are available inaccordance with the methods delineated in Kukolja, S. et al., Journal ofthe American Chemical Society, 97, pp. 3192-3198 (1975). The2β-halomethyl-2α-methylpenams have the formula ##STR5##

In accordance with the methods of Kukolja et al., the halomethylpenamsare prepared from penicillins by oxidation to their correspondingpenicillin sulfoxides. The latter, upon treatment with the thionylchloride and triethylamine in boiling carbon tetrachloride, producecompound II above in which X is chloro.

Thermolysis of the penicillin sulfoxide to produce the correspondingsulfenic acid, and treatment of the latter with phosphorus tribromide indichloromethane at room temperature produces a compound of formula IIabove in which X is bromo.

In addition, Kukolja et al., supra, describe the reaction of a compoundof formula ##STR6## with thionyl chloride in the presence oftriethylamine to produce a compound of formula II above in which X ischloro.

As the Kukolja et al. publication indicates, the compounds of formula IIexhibit a lack of stability, rearranging over a period of time to thecorresponding 3β-halo-3α-methylcephams. Therefore, the possibility touse these compounds as precursors to the intermediate azetidin-2-ones ofthis invention is fleeting, and their conversion to the azetidine-2-onesof this invention must be carried out reasonably soon after preparation.

Once the compounds of formula II have been prepared, their conversion tothe intermediate azetidin-2-ones of this invention is accomplished bythe following sequence: ##STR7##

The first step in the sequence involves the oxidation of an ester of a6-imido-2β-halomethyl-2α-methylpenam-3-carboxylic acid II to thecorresponding sulfoxide. This oxidation is carried out in accordancewith the well-recognized techniques employed in oxidation of a typicalpenicillin to its corresponding penicillin sulfoxide. Thus, thehalomethylpenam is reacted in an appropriate solvent with a molarequivalent of m-chloroperbenzoic acid, the reaction typically beingcarried out at a low temperature. The reaction is monitored by means ofthin-layer chromatography (TLC) which permits a periodic and currentmeasure of the extent of conversion from the sulfide to thecorresponding sulfoxide. When TLC confirms that the reaction isessentially complete, the resulting reaction mixture is worked up inaccordance with recognized techniques to recover the desired product.

The product, an ester of a6-imido-2β-halomethyl-2α-methylpenam-3-carboxylate-1α-oxide (IV), thenis converted to the azetidin-2-one of this invention. The azetidin-2-oneis prepared by reacting the α-sulfoxide (IV) with2-mercaptobenzothiazole at an elevated temperature. The reaction iscarried out by mixing from about 0.9 to about 1.5 moles and, preferably,about 1.0 to about 1.1 moles, of the mercapto compound with each mole ofthe halomethylpenam sulfoxide ester. The resulting mixture, preferablydissolved in a suitable inert solvent, is heated to a temperature offrom about 40° C. to about 110° C., and preferably from about 70° C. toabout 90° C. Suitable solvents are those having a boiling point at leastas high as the temperature of reaction. Included among such solventsare, for example, aromatic hydrocarbons such as benzene and toluene;halogenated hydrocarbons such as carbon tetrachloride, chlorobenzene,bromobenzene, bromoform, chloroform, ethylene dichloride, ethylenedibromide, and the like; amides, such as N,N-dimethylformamide,N,N-dimethylacetamide, and the like; aliphatic nitriles, such asacetonitrile, propionitrile, and the like; esters, such as ethylacetate, and the like; ethers, such as dioxane, and the like; and anyother appropriate inert solvents. Preferred solvents are those having aboiling point within the range of the temperature at which the reactionis to be carried out, thereby permitting the reaction mixture to berefluxed while retaining temperature control.

The resulting reaction mixture generally is heated at a temperature inthe defined range for a period of from about 0.5 to about 4 hours, andpreferably for a period of from about 0.5 to about 1.5 hours. Theproduct which forms generally crystallizes from the reaction mixture andcan be readily filtered off. However, the novel azetidin-2-oneintermediate also can be isolated from the reaction mixture byevaporating the reaction mixture in vacuo to remove solvent from thesystem and treating the residue in accordance with readily recognizedtechniques including extraction, recrystallization, chromatography, andthe like.

The azetidin-2-ones which result from the aforedescribed reaction havethe formula I above and specifically are those compounds in which thegroup R₂ of the broad definition of the compounds of this invention ismethylene. These azetidin-2-ones represent one facet of the invention ofthis application. For the sake of convenience these azetidin-2-ones willbe referred to herein by the shorthand term "methylene azetidinones".

Examples of methylene azetidinones of this invention include:4-(2'-benzothiazolyldithio)-3-phthalimido-1-(1'-methoxycarbonyl-2'-chloromethylprop-2'-enyl)azetidin-2-one;4-(2'-benzothiazolyldithio)-3-phthalimido-1-[1'-(p-nitrobenzyloxycarbonyl)-2'-bromomethylprop-2'-enyl]azetidin-2-one;4-(2'-benzothiazolyldithio)-3-phthalimido-1-[1'-(p-nitrobenzyloxycarbonyl)-2'-chloromethylprop-2'-enyl]azetidin-2-one;4-(2'-benzothiazolyldithio)-3-succinimido-1-(1'-benzyloxycarbonyl-2'-chloromethylprop-2'-enyl)azetidin-2-one;4-(2'-benzothiazolyldithio)-3-phthalimido-1-(1'-benzyhydryloxycarbonyl-2'-bromomethylprop-2'-enyl)azetidin-2-one;4-(2'-benzothiazolyldithio)-3-glutarimido-1-[1'-(t-butyloxycarbonyl)-2'-chloromethylprop-2'-enyl]azetidin-2-one;4-(2'-benzothiazolyldithio)-3-adipimido-1-[1'-(p-nitrobenzyloxycarbonyl)-2'-chloromethylprop-2'-enyl]azetidin-2-one;4-(2'-benzothiazolyldithio)-3-(3'-bromophthalimido)-1-(1'-benzhydryloxycarbonyl-2'-bromomethylprop-2'enyl)-azetidin-2-one;4-(2'-benzothiazolyldithio)-3-(4'-iodophthalimido)-1-[1'-(p-nitrobenzyloxycarbonyl)-2'-chloromethylprop-2'-enyl]azetidin-2-one;4-(2'-benzothiazolyldithio)-3-(3'-methylphthalimido)-1-[1'-(p-methoxybenzyloxycarbonyl)-2'-2'-bromomethylprop-2'enyl]azetidin-2-one;4-(2'-benzothiazolyldithio)-3-(4'-chlorophthalimido)-1-(1'-phthalimidomethoxycarbonyl-2'-chloromethylprop-2'-enyl)azetidin-2-one;4-(2'-benzothiazolyldithio)-3-hexahydrophthalimido-1-(1'-succimidomethoxycarbonyl-2'-bromomethylprop-2'-enyl)acetidin-2-one;4-(2'-benzothiazolyldithio)-3-malonimido-1-[1'-(2'-iodoethoxycarbonyl)-2'-chloromethylprop-2'-enyl]-azetidin-2-one;4-(2'-benzothiazolyldithio)-3-(1',2',3',6'-tetrahydrophthalimido)-1-(1'-pivaloyloxymethoxycarbonyl-2'-bromomethylprop-2'-enyl)azetidin-2-one;4-(2'-benzothiazolyldithio)-3-(3'-methylphthalimido)-1-(1'-acetoxymethoxycarbonyl-2'-chloromethylprop-2'-enyl)azetidin-2-one;4-(2'-benzothiazolyldithio)-3-(4'-methoxyphthalimido)-1-(1'-phenacyloxycarbonyl-2'-bromomethylprop-2'-enyl)azetidin-2-one;4-(2'-benzothiazolyldithio)-3-methylmalonimido-1-[1'-(p-nitrobenzyloxycarbonyl)-2'-bromomethylprop-2'-enyl]-azetidin-2-one;4-(2'-benzothiazolyldithio)-3-(4'-fluorophthalimido)-1-[1'-(p-nitrobenzyloxycarbonyl)-2'-chloromethylprop-2'-enyl]azetidin-2-one;4-(2'-benzothiazolyldithio)-3-(3'-isopropylphthalimido)-1-[1'-(p-nitrobenzyloxycarbonyl)-2'-chloromethylprop-2'-enyl]azetidin-2-one;4-(2'-benzothiazolyldithio)-3-(3'-fluorophthalimido)-1-[1'-(p-methoxybenzyloxycarbonyl)-2'-chloromethylprop-2'-enyl]azetidin-2-one;4-(2'-benzothiazolyldithio)-3-(1' ,4' ,5'6'-tetrahydrophthalimido)-1-[1'-(p-nitrobenzyloxycarbonyl)-2'-chloromethylprop-2'-enyl]azetidin-2-one;and the like.

Another facet of this invention comprises those azetidin-2-ones in whichthe group R₂ is oxygen, thereby defining a carbonyl moiety. Compounds inwhich R₂ is oxygen also participate in the invention of this applicationand have the formula ##STR8##

The azetidin-2-ones of formula V are prepared from the methyleneazetidinones. Those azetidin-2-ones will be referred to herein by theshorthand term "keto azetidinones". As indicated, the keto azetidinonesare prepared from the methylene azetidinones. This conversion isachieved by ozonolysis of the methylene azetidinone followed bydecomposition of the ozonide intermediate which is formed.

The aforementioned ozonolysis reaction can be depicted by the followingsequence: ##STR9##

Specifically, this reaction can be carried out by passing ozone througha solution of the methylene azetidinone (VI) in an inert solvent at atemperature of from about -80° C. to about 0° C. The methylene doublebond reacts with ozone to form in situ an intermediate ozonide which isdecomposed, as hereinafter described, to form the keto azetidinone ofFormula V. In the above formulae, R, R₁, and Z are as hereinbeforedescribed.

Ozone is prepared by means of an ozone generator of the type commonlyused in synthetic and analytical chemical work. The ozone is produced bythe action of an electric discharge on oxygen. One such ozone generatoris that manufactured by the Welsback Corporation. The ozone is generatedin a stream of oxygen which then is passed directly into the reactionvessel. The percentage of ozone contained in the oxygen stream can bevaried as desired, for example, by varying the rate of flow of oxygenthrough the ozonizer as well as by varying the intensity of the electricdischarge. The percentage of ozone in the oxygen stream can bedetermined iodimetrically. The amount of iodine liberated by thegenerated ozone from a standard solution of potassium iodide isdetermined by titration with sodium thiosulfate. The percentage of ozonein the oxygen stream is not critical; however, for convenience incarrying out the ozonolysis, an estimate of the amount of ozone flowinginto the reaction mixture enables one to determine the time at which thedesired reaction should be complete and thus minimizes any possibilityof formation of over-oxidation products.

Alternatively, the ozonolysis reaction can be followedchromatographically. For instance, a small aliquot of the reactionmixture is withdrawn, the ozonide is decomposed, and the amount ofunreacted starting material and keto azetidinone product present in thesample is assessed by a comparison of the thin-layer chromatogram withthat of a known amount of starting material and keto azetidinonecompound.

Inert solvents which can be used in the ozonolysis reaction are thosesolvents in which the methylene azetidinone is at least partiallysoluble and which are unreactive with ozone under the definedconditions. Commonly used organic solvents such as methanol, ethanol,ethyl acetate, methyl acetate, and methylene chloride are satisfactory.The concentration of the methylene azetidinone starting material in theinert solvent is not critical, and it is preferred to use a solventvolume sufficient to form complete solution. Preferably, the temperatureof reaction for the ozonolysis is at the lower range, generally betweenabout -80° C. and about -50° C.

When ozonide formation is complete, as determined by any of the methodsdescribed above, any excess ozone present in the reaction mixture ispurged from the mixture by bubbling nitrogen or oxygen through themixture.

Following the removal of excess ozone, the ozonide is decomposed byadding to the reaction mixture a mild reducing agent such as sodiumbisulfite, sulfur dioxide, trimethyl phosphite, dimethyl sulfide, andthe like, to provide the corresponding keto azetidinone product. Thedecomposition is carried out by adding an excess of the reducing agentto the mixture and then stirring the reaction mixture at a temperatureof from about -80° C. to about 0° C. until the reaction mixture isnegative to a potassium iodide-starch test.

A preferred reagent for decomposing the intermediate ozonide is gaseoussulfur dioxide. This reagent is preferred since it is completelyvolatilized from the reaction mixture during the subsequent work-up andthus does not complicate the recovery of the reaction product.

The keto azetidinone product is recovered from the reaction mixture byfirst evaporating the mixture to dryness and then extracting the productfrom the residue. Alteratively, the product can be recovered from theorganic liquid phase of the decomposition mixture by separating theliquid phase from insolubles, and, after washing and drying, evaporatingthe organic layer to yield the keto azetidinone product.

In addition, it is pointed out that a tautomer of the keto azetidinonecan be drawn, the relationship being depicted as follows: ##STR10##

For the purposes of convenience and clarity, however, the abovecompounds will be referred to herein in their keto form.

Examples of ketoazetidin-2-ones of this invention include:4-(2'-benzothiazolyldithio)-3-phthalimido-1-(1'-methoxycarbonyl-2'-oxo-3'-chloropropyl)azetidin-2-one;4-(2'-benzothiazolyldithio)-3-phthalimido-1-[1'-(p-methoxybenzyloxycarbonyl)-2'-oxo-3'-bromopropyl]azetidin-2-one;4-(2'-benzothiazolyldithio)-3-phthalimido-1-[1'-(p-nitrobenzyloxycarbonyl)-2'-oxo--3'-chloropropyl]azetidin-2-one;4-(2'-benzothiazolyldithio)-3-succinimido-1-(1'-benzyloxycarbonyl-2'-oxo-3'-chloropropyl)azetidin-2-one;4-(2'-benzothiazolyldithio)-3-phthalimido-1-(1'-benzhydryloxycarbonyl-2'-oxo-3'-bromopropyl)azetidin-2-one;4-(2'-benzothiazolyldithio)-3-glutarimido-1-[1'-(t-butyloxycarbonyl)-2'-oxo-3'-chloropropyl]azetidin-2-one;4-(2'-benzothiazolyldithio)-3-adipimido-1-[1'-(p-nitrobenzyloxycarbonyl)-2'-oxo-3'-chloropropyl]azetidin-2-one;4-(2'-benzothiazolyldithio)-3-(3'-bromophthalimido)-1-(1'-benzhydryloxycarbonyl-2'-oxo-3'-bromopropyl)azetidin-2-one;4-(2'-benzothiazolyldithio)-3-(4'-iodophthalimido)-1-[1'-(p-nitrobenzyloxycarbonyl)-2'-oxo-3'-chloropropyl]azetidin-2-one;4-(2'-benzothiazolyldithio)-3-(3'-methylphthalimido)-1-[1'-(p-methoxybenzyloxycarbonyl)-2'-bromopropyl]azetidin-2-one;4-(2'-benzothiazolyldithio)-3-(4'-chlorophthalimido)-1-(1'-phthalimidomethoxycarbonyl-2'-oxo-3'-chloropropyl)-azetidin-2-one;4-(2'-benzothiazolyldithio)-3-hexahydrophthalimido-1-(1'-succinimidomethoxycarbonyl-2'-oxo-3'-bromopropyl)azetidin-2-one;4-(2'-benzothiazolyldithio)-3-malonimido-1-[1'-(2"-iodoethoxycarbonyl)-2'-oxo-3'-chloropropyl]azetidin-2-one;4-(2'-benzothiazolyldithio)-3-(1',2',3',6'-tetrahydrophthalimido)-1-(1'-pivaloyloxymethoxycarbonyl-2'-oxo-3'-bromopropyl)azetidin-2-one;4-(2'-benzothiazolyldithio)-3-(3'-methylphthalimido)-1-(1'-acetoxymethoxycarbonyl-2'-oxo-3'-chloropropyl)azetidin-2-one;4-(2'-benzothiazolyldithio)-3-(4'-methoxyphthalimido)-1-(1'-phenacyloxycarbonyl-2'-oxo-3'-bromopropyl)azetidin-2-one;4-(2'-benzothiazolyldithio)-3-methylmalonimido-1-[1'-(p-nitrobenzyloxycarbonyl)-1'-oxo-3'-bromopropyl]-azetidin-2-one;4-(2'-benzothiazolyldithio)-3-glutarimido-1[1'-(p-nitrobenzyloxycarbonyl)-2'-oxo-3'-chloropropyl]-azetidin-2-one;4-(2'-benzothiazolyldithio)-3-(3'-isopropylphthalimido)-1-[1'-(p-nitrobenzyloxycarbonyl)-2'-oxo-3'-chloropropyl]azetidin-2-one;4-(2'-benzothiazolyldithio)-3-(3'-fluorophthalimido)-1-[1'-(p-methoxybenzyloxycarbonyl)-2'-oxo-3'-chloropropyl]azetidin-2-one;4-(2'-benzothiazolyldithio)-3-(1',4',5',6'-tetrahydrophthalimido)-1-[1'-p-nitrobenzyloxycarbonyl)-2'-oxo-3'-chloropropyl)-azetidin-2-one;and the like.

The azetidin-2-ones of this invention are useful as intermediates in thepreparation of the corresponding 3-exomethylenecephams and3-ketocephams. This conversion is accomplished in accordance with thefollowing sequence: ##STR11##

As is true with respect to the ketoazetidin-2-one, the 3-ketocepham (R₂equals oxygen) also gives rise to a tautomerism. Thus, the 3-ketocephamcan be drawn in the form of its 3-hydroxy-3cephem structure.

In carrying out the ring-closure of the azetidin-2-one of thisinvention, the compound generally is reacted with sodium iodide orpotassium iodide in a ketone solvent. Typical such ketone solventsinclude acetone, methyl ethyl ketone, and the like. The solventpreferred for use is acetone. The azetidin-2-one is dissolved in asuitable quantity of the selected solvent. At least a molar quantity ofthe iodide salt is added and, generally, an excess representingapproximately a 2:1 molar ratio of the iodide salt to the azetidin-2-onestarting material is employed. The reaction mixture is heated to atemperature from about 40° C. to about 80° C. and preferably to atemperature within the range from about 50° C. to about 60° C., and theresulting mixture is allowed to react at the selected temperature for aperiod of from about 24 hours to about 48 hours. Generally, the reactionis complete after about 40 hours. The extent of reaction can bemonitored quite conveniently by thin-layer chromatograpny (TLC) analysisof an aliquot of the reaction mixture at appropriate points during thecourse of the reaction.

The product is recovered from the reaction mixture in accordance withwell-recognized techniques which may include evaporation of the solventand extractive separation of the product from the residue which remains.

As indicated above, the structure of the product will be either a3-exomethylenecepham or a 3-ketocepham depending upon the identity ofthe group R₂ in the azetidin-2-one starting material. In the event thatthe product which is obtained is a 3-exomethylenecepham, this productcan be converted in accordance with known techniques to thecorresponding 3-ketocepham compound. These techniques involve ozonolysisof the 3-exomethylenecepham under conditions substantially identical tothose delineated hereinabove for conversion of the methyleneazetidin-2-one to its corresponding keto azetidin-2-one.

The 3-exomethylenecephams and the 3-ketocephams (3-hydroxy-3-cephems)prepared from the azetidin-2-ones of this invention are well recognizedin the art as useful in the production of antibiotically activecompounds. These compounds and their utility are described in detail inChauvette, R. R., and Pennington, P. A., Journal of Organic Chemistry,38, 2994 (1973); and Chauvette, R. R., and Pennington, P. A., Journal ofthe American Chemical Society, 96, 4986 (1974).

The invention of this application is illustrated by the examples whichfollow. It is not intended that the invention in any way be limited byreason of the following examples.

EXAMPLE 1 Preparation of Methyl6-phthalimido-2β-chloromethyl-2α-methylpenam-3-carboxylate.

To 500 ml. of dry carbon tetrachloride were added 10 grams of methyl7-phthalimido-3β-hydroxy-3α-methylcepham-4-carboxylate and 3.43 ml. ofthionyl chloride. The resulting mixture was heated to reflux, and 4.26ml. of triethylamine in 100 ml. of carbon tetrachloride were added overa 1-hour period. The above sequence was repeated using a separate batchof materials, and the resulting reaction mixtures were combined andevaporated to dryness. The residue was taken up in 250 ml. of ethylacetate, and the ethyl acetate solution was washed twice with 250 ml. ofwater and then with 25 ml. of brine. The mixture then was dried overmagnesium sulfate and evaporated to about one-half volume. A tan powderprecipitated and was collected by filtration. The filtrate was thenevaporated to dryness, and the residue was recrystallized from a 1:5mixture of ethyl acetate and ethyl ether to obtain 11.22 grams of thetitle compound.

EXAMPLE 2 Preparation of Methyl6-phthalimido-2β-chloromethyl-2α-methylpenam-3-carboxylate-1.alpha.-oxide.

To 200 ml. of methylene chloride were added 11.22 grams (28.4 mmoles) ofmethyl 6-phthalimido-2β-chloromethyl-2α-methylpenam-3-carboxylate.Methylene chloride (100 ml.) containing 5.68 grams (28.4 mmoles) ofm-chloroperbenzoic acid was added, and the resulting mixture was stirredfor one hour at ice bath temperature. The reaction mixture then waswashed successively with 50 ml. of 5 percent aqueous sodium sulfite,twice with 50 ml. of 5 percent sodium bicarbonate, 100 ml. of water, and100 ml. of brine. The mixture then was dried over magnesium sulfate andevaporated to give 11.54 grams (28.1 mmoles) of the title compound.

NMR (CDCl₃) δ 1.41 (s, --CH₃), 3.81 (s,--OMe), 4.14 (s,--CH₂ Cl), 4.92(s, H-3), 4.96 (d, 1H, J=4.5 Hz.) 5.93 (d, 1H, J=4.5 Hz., and 7.81 Hz.(m, 4 aromatic H).

EXAMPLE 3 Preparation of4-(2'-Benzothiazolyl-dithio)-3-phthalimido-1-(1'-methoxycarbonyl-2'-chloromethyl-prop-2'-enyl)azetidin-2-one.

To 150 ml. of benzene were added 11.54 grams (28.1 mmoles) of methyl6-phthalimido-2β-chloromethyl-2α-methylpenam-3-carboxylate-1.alpha.-oxide.To the resulting mixture then were added 4.7 grams (28.1 mmoles) of2-mercaptobenzothiazole. The mixture was heated to reflux for 30minutes, and the resulting mixture then was evaporated to give the titlecompound as a light yellow foam.

NMR (CDCl₃) δ 3.81 (s,--OMe), 4.3 and 4.5 (dd, --CH₂ Cl, J=12 Hz.), 5.43(s, 1H), 5.53 (s, 1H), 5.65 (s, 1H), 5.98 (s, 2 azet. H) and 7.81 Hz (m,4 aromatic H).

EXAMPLE 4 Preparation of Methyl7-Phthalimido-3-methylenecepham-4-carboxylate.

To a solution of 1.12 grams (2 mmoles) of4-(2'-benzothiazolyldithio)-3-phthalimido-1-(1'-methoxycarbonyl-2'-chloromethylprop-2'-enyl)azetidin-2-one in 75 ml. of acetone wasadded 0.50 grams (3 mmoles) of potassium iodide. The mixture wasrefluxed for three days after which TLC of the reaction mixture showed aspot indicating the presence of unreacted starting material. Anadditional 0.5 grams of potassium iodide was added, and refluxing wascontinued for an additional day during which time TLC established thatno change in the reaction mixture was effected. The mixture wasevaporated to dryness, and the residue was taken up in 50 ml. of ethylacetate. The ethyl acetate solution was washed successively with 25 ml.of 0.1 N sodium bisulfite solution, 25 ml. of water, and 25 ml. ofbrine. The ethyl acetate solution then was dried over sodium sulfate andevaporated to give 1.05 grams of the title compound as a tan foam.

NMR (CDCl₃) δ 3.35 and 3.6 (dd, --CH₂ S, J=13 Hz.), 3.8 (s,--OMe), 5.3(m, 3H), 5.5 (d, 1H, J=4.5 Hz.), 5.68 (d, 1H, J=4.5 Hz.) and 7.8 Hz. (m,4 aromatic H).

EXAMPLE 5 Preparation of4-(2'-Benzothiazolyldithio)-3-phthalimido-1-(1'-methoxycarbonyl-2'-oxo-3'-chloropropyl)azetidin-2-one.

A solution of 1.12 g. (2 mmole) of4-(2'-benzothiazolyldithio)-3-phthalimido-1-(1'-methoxycarbonyl-2'-chloromethylprop-2'-enyl)azetidin-2-onein 100 ml. of CH₂ Cl₂ was cooled in an acetone-dry ice bath and ozonewas introduced into this solution from a generator for 5 minutes. Inorder to reduce a formed ozonide, sulfur dioxide gas was passed throughthe solution for 2 minutes. The mixture then was warmed to roomtemperature and was washed with water and brine. After drying overMgSO₄, the solvent was evaporated to give 870 mg. of the title compound.

NMR (CDCl₃) δ 3.75 (s,--OMe), 4.45 and 4.75 (dd, --CH₂ Cl, J=12 Hz.),5.78 (d, 1H, J=5 Hz.), and 5.97 Hz. (d, 1H, J=5 Hz.).

EXAMPLE 6 Preparation of Methyl7-Phthalimido-3-ketocepham-4-carboxylate.

A solution of 870 mg. of4-(2'-benzothiazolyldithio)-3-phthalimido-1-(1'-methoxycarbonyl)-2'-oxo-3'-chloropropyl)azetidin-2-oneand 500 mg. of potassium iodide in 40 ml. of acetone was refluxed for 20hours. The solvent was evaporated, and the residue was dissolved in amixture of 50 ml. of ethyl acetate and 10 ml. of brine and dried overMgSO₄. The solvent was evaporated to give methyl7-phthalimido-3-keto-cepham-4-carboxylate.

NMR (CDCl₃) δ 2.93 and 4.07 (dd,--CH₂ S, J=15 Hz.), 3.8 (s, 3, --OMe),5.22 d, 1H, J=4.5 Hz.) 5.75 d, 1H, J=4.5 Hz.), and 7.8 Hz. (m, 4aromatic H).

EXAMPLE 7 Preparation of p-Nitrobenzyl6-Phthalimido-2β-bromomethyl-2α-methylpenam-3-carboxylate-1.alpha.-oxide.

To about 20 ml. of chloroform were added about one gram of p-nitrobenzyl6-phthalimido-2β-bromomethyl-2α-methylpenam-3-carboxylate. The resultingsolution was cooled in an ice bath, and 500 mg. (2.5 mmoles) ofm-chloroperbenzoic acid in 10 ml. of chloroform were added dropwise. Theresulting mixture was stirred in the ice bath for about 1 hour. Themixture then was washed successively with 50 ml. of 5 percent sodiumbisulfite, twice with 50 ml. of saturated aqueous sodium bicarbonate,with 50 ml. of water, and with 25 ml. of brine. The mixture then wasdried over magnesium sulfate and evaporated in vacuo at 25° C. to givethe title compound as a white foam.

EXAMPLE 8 Preparation of4-(2'-Benzothiazolyl-dithio)-3-phthalimido-1-[1'-(p-nitrobenzyloxycarbonyl)-2'-bromomethylprop-2'-enyl]azetidin-2-one.

A mixture of 1.15 grams (2 mmoles) ofp-nitrobenzyl-6-phthalimido-2β-bromomethyl-2α-methylpenam-3-carboxylate-1α-oxideand 340 mg. (2 mmoles) of 2-mercaptobenzothiazole in 25 ml. of benzenewas prepared. The mixture was refluxed for 60 minutes and then wascooled and transferred to another flask and kept at room temperature forabout 1 hour. Approximately 100 mg. of solid was filtered, and thefiltrate was evaporated to give 0.7 grams of the title compound as aslightly yellow foam.

NMR (CDCl₃) δ 4.42 (m,---CH₂ Br), 5.3 (s, 1H), 5.35 (s,CH₂ of pNB), 5.6(s, 1H), 5.65 (s, 1H), 5.81 (d, 1H, J=4.5 Hz.), 5.9 (d, 1H, J=4.5 Hz.)and 7.4-8.3 Hz. (m, aromatic H).

EXAMPLE 9 Preparation of p-Nitrobenzyl6-Phthalimido-2β-chloromethyl-2α-methylpenam-3-carboxylate-1.alpha.-oxide.

To 200 ml. of methylene chloride were added 6.45 grams (12 mmoles) ofp-nitrobenzyl6-phthalimido-2β-chloromethyl-2α-methylpenam-3-carboxylate. An insolubleportion of approximately 100-200 mg. was filtered off, and 2.4 grams (12mmoles) of m-chloroperbenzoic acid were added. The mixture was stirredfor about 30 minutes and then was washed successively with aqueoussodium bicarbonte and aqueous sodium chloride. The mixture was driedover magnesium sulfate and evaporated. The residue was dissolved in amixture of 10 ml. of methylene chloride and 3 ml. of cyclohexane. Theinsolubles were filtered off, and the solvent was evaporated to give 5.6grams of the title compound.

EXAMPLE 10 Preparation of4-(2'-Benzothiazolyl-dithio)-3-phthalimido-1-[1'-(p-nitrobenzyloxycarbonyl)-2'-chloromethylprop-2'-enyl]azetidin-2-one.

A mixture of 5.32 grams (10 mmoles) of p-nitrobenzyl6-phthalimido-2β-chloromethyl-2α-methylpenam-3-carboxylate-1.alpha.-oxideand 1.7 grams (10 mmoles) of 2-mercaptobenzothiazole in 100 ml. ofbenzene was prepared. The mixture was refluxed for 50 minutes, and theresulting clear, warm solution was transferred to another flask and wasallowed to stand overnight. Crystals (4.5 grams) of the title compoundwere collected by filtration and shown by TLC to be one spot material.

NMR (CDCl₃) δ 4.23 and 4.5 (dd,-CH₂ Cl, J=12 Hz), 5.3 (s,1H), 5.33(s,-CH₂ of pNB), 5.5 (s, 1H), 5.6 (s, 1H), 5.75 (d, 1H, J=4.5 Hz.), 5.85((d, 1H, J=4.5 Hz.), and 7.4-8.3 Hz. (m, 8 aromatic H).

EXAMPLE 11 Preparation of p-Nitrobenzyl7-Phthalimido-3-exomethylenecepham-4-carboxylate.

A mixture of 1.3 grams of4-(2'-benzothiazolyl-dithio)-3-phthalimido-1-[1'-(p-nitrobenzyloxycarbonyl)-2'-chloromethylprop-2'-enyl]azetidin-2-oneand 400 mg. of potassium iodide in 70 ml. of acetone was prepared. Themixture was refluxed, and a TLC of the reaction mixture after 19 hoursof reflux indicated that approximately one-half of the starting materialremained. Refluxing was continued for a total of 44 hours after whichtime a TLC of the reaction mixture indicated that the starting materialwas gone. The solution was evaporated, and the residue was dissolved inethyl acetate. The ethyl acetate solution was washed successively withaqueous sodium thiosulfate, water, aqueous sodium bicarbonate, andaqueous sodium chloride. The ethyl acetate solution then was dried overmagnesium sulfate and evaporated to give 0.9 grams of a residue. Theresidue was dissolved in 5 ml. of toluene after which crystallizationbegan to occur, and 200 mg. of the title compound was collected byfiltration and recrystallized from a mixture of 5 ml. of benzene and 2ml. of chloroform. Crystals of the title compound were collected andagain were recrystallized from a mixture of 4 ml. of benzene and 3 ml.of chloroform.

The toluene filtrate was evaporated, and the residue (650 mg.) waschromatographed over a silica gel column (1.5 × 30 cm.) and eluted witha 9:1 mixture of toluene and ethyl acetate to obtain an additional 300mg. of the title compound.

NMR (CDCl₃) δ 3.3 and 3.62 (dd,-CH₂ S, J=14 Hz.), 5.37 (s, 5H), 5.43 (d,1H, J=4.5 Hz.), 5.62 (d, 1H, J=4.5 Hz.), and 7.4-8.3 Hz. (m, 8 aromaticH).

EXAMPLE 12 Preparation of4-(2'-Benzothiazolyldithio)-3-phthalimido-1-[1'-(p-nitrobenzyloxycarbonyl)-2'-oxo-3'-chloropropyl]azetidin-2-one.

A solution of 650 mg. of 4-(2'-benzothiazolyldithio)-3-phthalimido-1-[1'-(p-nitrobenzyloxycarbonyl)-2'-chloromethylpropy-2'-enyl]azetidine-2-oneand 100 ml. of CH₂ Cl₂ was cooled in an acetone-dry ice bath, and ozonewas introduced until a blue color appeared (3-5 min.). Sulfur dioxidegas then was passed through the solution for 2 minutes, and the mixturewas warmed to room temperature. The mixture then was washed with waterand a brine solution. After drying over MgSO₄, the solvent wasevaporated to yield the title compound.

EXAMPLE 13 Preparation of p-Nitrobenzyl7-Phthalimido-3-hydroxy-3-cephem-4-carboxylate.

A solution of 350 mg. of p-nitrobenzyl7-phthalimido-3-exomethylenecepham-4-carboxylate in 100 ml. ofchloroform was prepared and then was cooled in a dry ice-acetone bath.Ozone then was passed through the mixture for 2-3 minutes until thecolor of the mixture turned blue. Sulfur dioxide gas was passed throughthe solution for about two minutes, and magnesium sulfate then was addedto the solution. The solution was brought to room temperature andfiltered. The filtrate was evaporated to give 270 mg. of the titlecompound as a colorless solid containing the corresponding sulfoxide asa minor contaminant.

NMR (CDCl₃) δ 2.95 and 4.02 (dd, CH₂ S, J=15 Hz.), 5.25 (d, 1H, J=4.5Hz.), 5.4 (s, CH₂ of pNB), 5.76 (d, 1H, J=4.5 Hz.), and 7.6-8.3 Hz. (m,8 aromatic H).

I claim:
 1. A process for preparing a cepham compound which comprisesreacting a compound of the formula ##STR12## with at least a molar ratioof sodium or potassium iodide at a temperature of from about 40° C. toabout 80° C., to produce the 3-exomethylene or 3-keto cepham of theformula ##STR13## in which, in the above formulae, R₁ is a carboxyprotecting group; R is the residue of an imide derived from adicarboxylic acid; R₂ is =CH₂ or =O; and X is chloro or bromo. 2.Process of claim 1, in which the reaction is carried out in the presenceof a ketone solvent.
 3. Process of claim 2, in which the reaction iscarried out in the presence of acetone.
 4. Process of claim 2, in whichR₁ is the residue of an ester function which is removable by acidtreatment or hydrogenation.
 5. Process of claim 2, in which R₁ ismethyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, benzylhydryl, t-butyl,or trimethylsilyl.
 6. Process of claim 2, in which R₁ is p-nitrobenzyl.7. Process of claim 2, in which R is phthalimido.
 8. Process of claim 7,in which R₂ is =CH₂.
 9. Process of claim 8, in which X is chloro. 10.Process of claim 7, in which R₂ is =O.
 11. Process of claim 10, in whichX is chloro.